ASTHMA

MA. LARRIZA A. FURIO-CASTRO

Asthma

chronic inflammatory disorder of the airways infiltration of mast cells, eosinophils and lymphocytes wheeze, cough, chest tightness and shortness of breath

symptoms vary over time and in severity

widespread, variable and reversible airflow limitation airway hyperresponsiveness common disease especially in children

GINA Guidelines 1998

Pathophysiology: cellular level

Allergen

Macrophage/ dendritic cell

Th2 cell

Mast cell

Neutrophil Eosinophil

Mucus plug Nerve activation Epithelial shedding

Subepithelial fibrosis Plasma leak Oedema Sensory nerve activation Cholinergic reflex Bronchoconstriction Hypertrophy / hyperplasia

Mucus hypersecretion Hyperplasia

Vasodilatation New vessels

Barnes PJ

Inflammatory processes

Barnes PJ

Epidemiology / pathology

Pathophysiology
chemical mediators

bronchoconstriction, mucosal edema,excessive secretions

Airway obstruction

Nonuniform ventilation
atelectasis

hyperinflation

Ventilation and perfusion mismatch

Decreased complicance
Increased work of breathing

Decreased surfactant
Pulmoary vasoconstriction

acidosis
Alveolar hypoventilation
Pco2 Po2

Risk factors that lead to asthma development

Predisposing Factors

Contributing Factors
respiratory infections small size at birth diet air pollution smoking

Hereditary/genes

Causal Factors

indoor allergens

dust mites animal dander cockroach fungi pollens fungi

passive active

outdoor allergens

occupational sensitisers

GINA Guidelines 1998

Common occupational agents

flour / grain dust (bakery) paint, glue or plastic fumes soldering flux natural rubber latex

wood dust

Clinical manifestations
The onset of an asthma exacerbation
may be acute or insidious during younger childhood. Acute episodes are most often caused exposure to irritants or allergens. Exacerbation precipitated by viral respiratory infections are slower in onset.

Cough, wheezing, tachypnea,

Signs and symptoms of asthma

dyspnea with prolonged expiration and use of accessory muscles of respiration, cyanosis, hyperinflation of the chest, tachycardia. Wheezing may be absent in extreme respiratory distress, only after bronchodilator treatment wheeze can occur again.

Between exacerbations the child may

be entirely free of symptoms and have no evidence of pulmonary disease on physical examination.

A barrel chest deformity is a sign of

the chronic, unremitting airway obstruction of severe asthma.

Laboratory evaluation

Eosinophilis of more than

300*106/L in peripheral blood.

IgE levels may be increased

Both are indicative of asthma

Asthma:
diagnosis

Asthma diagnosis

history and pattern of symptoms physical examination measurements of lung function evaluation of allergic status

Is it asthma?

symptoms - vary over time and in severity:

cough wheeze

breathlessness
chest tightness

symptoms occur or worsen at night or after exposure to trigger colds go to the chest or take >10 days to clear

Ask about triggers

Symptoms can occur or worsen in the presence of: Others exercise viral infection smoke changes in temperature strong emotional expression

Allergens animal dander dust mites pollen fungi

aerosol chemicals
drugs (NSAIDs, -blockers)

Peak flow measurement

The best of three PEF measurements is compared with the normal predicted for that individual based on age, height and sex.

Importance of long-term peak flow measurements

establishes diagnosis and treatment assesses severity of an exacerbation

assesses response to treatment

evaluates how well asthma is controlled alerts patient to need for possible change in treatment

PEF curves

PEF (L / min)

Before bronchodilator After bronchodilator

Day
Morning Evening Diagnosis

Clinical exacerbation
PEF

Mild attack Acute severe attack

Exacerbation

Days
An acute severe attack of asthma refers to the onset of symptoms severe enough to require emergency treatment

Clinical classification of severity

Clinical features before treatment
Symptoms
Night-time symptoms

STEP 4
Severe persistent

Continuous Limited physical activity Daily Use b2-agonist daily Attacks affect activity >1 time a week but <1 time a day <1 time a week Asymptomatic and normal PEF between attacks

Frequent

STEP 3
Moderate persistent

>1 time a week

STEP 2
Mild persistent

>2 times a month

STEP 1
Intermittent

<2 times a month

Treatment goal: take control of asthma

no chronic symptoms no asthma attacks

no emergency visits
no need for quick relief (as needed) 2-agonist normal physical activity including exercise

lung function as close to normal as possible

no adverse effects from medicine

GINA Guidelines 1998

Treatment strategy

identify and avoid triggers that make asthma worse achieve control by selecting appropriate medication treat asthma attacks promptly and effectively

educate patients to manage their condition

monitor and modify asthma care to maintain effective long-term control

GINA Guidelines 1998

Pharmacological therapy
Relievers

Controllers

inhaled fast-acting 2-agonists inhaled anticholinergics

inhaled corticosteroids inhaled long-acting 2agonists inhaled cromones oral anti-leukotrienes oral theophyllines oral corticosteroids

RELIEVERS MEDICATION

Quick relief medicine or rescue medicine. Rapid acting bronchodilators that act to relieve bronchoconstriction.

ROUTE OF ADMINISTRATION

INHALATION

Pressurized metered dose inhalers ( MDI) MDI-plus-spacer Breath actuated MDI Dry powder inhalers Nebulised

ORAL

PARENTERAL

Short-acting inhaled B-agonist

Use intermittently to control episodes of bronchoconstriction Use only on impending asthma attack/during asthma attack

LONG ACTING b2 AGONIST

Mechanism of action: Bronchodilator Enhance mucociliary clearance Modulate mediators release from mast cells and basophils Example : Inhaled : Salmeterol , formeterol Oral : Bambuterol Salbutamol SR Terbutaline SR Clenbuterol

LONG ACTING b2 AGONIST

Inhaled b2 Agonists have fewer side effects than oral formulations.

Side-effects : tachycardia, palpitations, tremors, anxiety, headache and hypokalaemia.

CONTROLLER MEDICATIONS

Are medications taken daily on a long term basis that are useful in getting and keeping persistent asthma under control. Prophylactic, preventive or maintenance medications Include

Inhaled glucocorticosteroids Systemic glucocorticosteroids Theophylline Long acting inhaled b2 agonist Long acting oral b2 agonist Leukotriene modifiers

GLUCOCORTICOSTEROIDS

Mechanisms of action :

Reduced airway inflammation Efficacy in improving lung function, decreasing airways hyperresponsiveness, reducing symptoms, reducing frequency and severity of exacerbations and improving quality of life.

GLUCOCORTICOSTEROID

Inhaled : Beclomethasone Budesonide Fluticasone

Oral : Prednisolone Dexamethasone

Parenteral : Hydrocortisone Methylprednisolone

Side effects Local effects oropharyngeal candidiasis, dysphonia, upper airway irritation

How to prevent ? Mouth washing after inhalation & use of spacer

Systemic adverse effects depends on the dose and potency of glucocrticosteroids , absorption in the gut, first past effect of liver.

Systemic adverse effects include : skin thinning, easy bruising, cataract, obesity, adrenal suppression, hypertension, diabetes and myopathy.

METHYLXANTHINES

Mechanism of action: Antiinflammatory effects & bronchodilator. Side effects :

GIT Symptoms nausea, vomiting CVS Symptoms tachycardia, arrhythmias Drug interaction : Erythromycin, cimetidine and rifampicin

Anti-cholinergics

Inhaled ipratropium bromide. Mechanism of action : Bronchodilator. Efficacy : Bronchodilator actions are less potent than those of inhaled 2-agonists, slower onset of action which peaks 30 60 min. Side-effect : Dry mouth.

LEUKOTRIENE MODULATORS

MECHANISM OF ACTION :

Block the synthesis of all leukotrienes

Example : montelukast ( Singulair ), Zafirlukast

STEP 4: SEVERE PERSISTENT

CONTROLLER: daily multiple medications Inhaled steroid Long-acting bronchodilator Oral steroid

RELIEVER Inhaled 2agonist p.r.n.

Step down when controlled

Avoid or control triggers STEP 3: MODERATE PERSISTENT

CONTROLLER: daily medications Inhaled steroid and long-acting bronchodilator Consider anti-leukotriene

RELIEVER Inhaled 2agonist p.r.n.

Avoid or control triggers STEP 2: MILD PERSISTENT

CONTROLLER: daily medications Inhaled steroid Or possibly cromone, oral theophylline or anti-leukotriene

RELIEVER Inhaled 2agonist p.r.n.

Patient education essential at every step Reduce therapy if controlled for at least 3 months Continue monitoring

Avoid or control triggers STEP 1: INTERMITTENT CONTROLLER: none RELIEVER Inhaled 2agonist p.r.n.

Avoid or control triggers TREATMENT GINA Guidelines 1998

Step up if not controlled (after check on inhaler technique and compliance)

Step 1
Step 1: Intermittent asthma
Controller

Reliever
Inhaled b2-agonist prn (not more than 3x a week) Inhaled b2-agonist or cromone prior to exercise or allergen exposure

None required

Avoid or control triggers

If asthma symptoms are intermittent, then reliever therapy alone is sufficient.

Step 2
Step 2: Mild persistent asthma
Controller
Daily inhaled corticosteroid (200-500 mg), cromone, sustained release theophylline, or anti-leukotriene

Reliever
Inhaled b2-agonist prn (but less than 3-4 times per day)

If still not controlled, particularly nocturnal symptoms, increase inhaled steroid (500-800 mg) or add long-acting bronchodilator

Avoid or control triggers

It is often best to initiate an inhaled steroid early and at a high dose to establish rapid control and then reduce the dose.

Step 3
Step 3: Moderate persistent asthma
Controller
Daily inhaled corticosteroid > 500 mg Daily long-acting bronchodilator Consider anti-leukotriene

Reliever
Inhaled b2-agonist prn (but less than 3-4 times per day)

Avoid or control triggers

A long-acting inhaled 2-agonist is the first choice add on therapy to inhaled steroids

Step 4
Step 4: Severe persistent asthma
Controller
Daily inhaled corticosteroid 800-2000 mg Daily long-acting bronchodilator Daily / alternate day oral corticosteroid

Reliever
Inhaled b2-agonist prn (but less than 3-4 times per day)

Avoid or control triggers

Patients with severe persistent asthma are often poorly controlled despite using combinations of all available controller medications.

Summary guidelines

gain control step up if control is not achieved and sustained step down if control is sustained for at least 3 months review treatment every 3-6 months

THE FACET STUDY

A total of 825 adult patients with moderate-tosevere asthma were randomised into 4 treatment groups based on bid doses as follows : - budesonide 100 ug bid + placebo - budesonide 100 ug bid + formorterol 9 ug bid - budesonide 400 ug bid + placebo - budesonide 400 ug bid + formorterol 9 ug bid

Adding formoterol to budesonide reduces rate of severe exacerbations

1
Exacerbations / patient / year
Increasing Pulmicort dose: p <0.001 Adding Oxis: p = 0.014 Pulmicort 800 vs. Pulmicort 200 + Oxis: p = 0.031

0.5

Pulmicort 100 mg bid

Pulmicort 100 mg bid + Oxis 9 mg bid

Pulmicort 400 mg bid

Pulmicort 400 mg bid + Oxis 9 mg bid

Pauwels et al, NEJM 1997

Adding formoterol to budesonide improves morning PEF 30

20

10

L / min

0 -10 -20 -30 0 1 2 3

Pulmicort 100 mg bid Pulmicort 400 mg bid Pulmicort 100 mg bid + Oxis 9 mg bid Pulmicort 400 mg bid + Oxis 9 mg bid

Months

12

Pauwels et al, NEJM 1997

Synergy between formoterol and budesonide

Conclusion

There is a synergistic effect on treatment when these agents are combined.

The combination of these agents also makes the treatment simpler for the patient, which may improve compliance.

Co-formulated products are generally less expensive than giving the two constituents separately.

Management of Asthma in Pregnancy.

Management of asthma during pregnancy should be aggressive. Cooperation between the resp. physician and obstetrcian throughout pregnancy for women with severe asthma.

Beta2 agonists. There is no evidence of a teratogenic risk. Ipratopium bromide / Sodium cromoglycate. Safe for use during pregnancy. Salmeterol/formoterol. Have not been tested extensively in pregnant women.

Theophyllines. May aggravate the nausea and gastroesophageal reflux. May cause transient neonatal tachycardia and irritability. Inhaled corticosteroids. Has good safety profile in pregnancy. Anti-leukotrienes. No data is available on the use of this agent in pregnant women.

Oral corticosteroids. Sometimes necessary for severe asthma but usually only for short periods. An increased risk of cleft palate has been reported in animals given huge doses. Breastfeeding. Should be continued in women with asthma. In general, asthma medications are safe during pregnancy and lactation and the benefits outweigh any potential risks to the fetus and baby.